Human stem cell-derived neurons (hSCNs) represent powerful, physiologically relevant cells for drug discovery, yet there is limited data on the proteins that form ion channels. Ion channels are the site of action of many therapeutic drugs and highly attractive targets for the development of new medicines for an array of disorders including epilepsy, dementia and stroke.
Ion channels also represent under-exploited drug targets primarily because their investigation depends on skilled electrophysiologists conducting time-consuming experiments with low data throughput for drug discovery. These technical challenges represent major bottlenecks to the identification and development of novel agents for neuropsychiatric disorders. Characterization of the ion channels present in hSCNs combined with the development of tools for high-throughput assays would therefore be a major advance in using stem cells in the drug discovery process.
Recently, several automated recording systems have been developed which greatly increase the number, speed and array of ion channels that can be studied. However, these automated machines are limited to the use of experimental cells expressing cloned channels.
Recent data show that hSCNs express protein markers and ion channels found in native neurons and these nerve cells can be grown and maintained in culture over long periods rendering them amenable to automated high speed investigation: development of hSCNs for automated physiological studies would thus enable simultaneous study of multiple ion channel drug targets in a single (standardized, human) neuron and greatly increase the sophistication of neurophysiological and neuropharmacological experimentation.
This proposal therefore aims to develop the methods and evaluate the suitability of human stem cell-derived neurons for automated patch-clamp electrophysiology studies.
The integration of stem cell technology with automated systems would be unique in California and yield significant improvements in ion channel screening, lead optimization and assessment of drug safety; it will also later provide key information on the consequences of genetic mutations in ion channels and the impact of culture conditions to guide the generation of specific cell type derivatives. The combination of automated electrophysiology with hSCNs for ion channel studies will significantly enhance the value of stem cells as tools in the drug discovery and biotech industry in California.
Statement of Benefit to California:
This proposal aims to develop the methods and evaluate the suitability of exploiting human stem cell-derived neurons for automated, high speed physiological studies of ion channels for drug discovery. Ion channels in nerve cells are highly attractive but under-exploited targets for the development of new medicines because they cannot be screened easily.
Success in this project will optimize the identification of new drug leads for neuropsychiatric illnesses and improve assessment of drug safety. These are major benefits to the citizens of California.
The biotech and pharmaceutical industry are significant contributors to the State economy and major employers in California. Leading the exploitation and development of stem cells as tools for drug discovery and development here will support job creation and significantly benefit our economy.
Utilization of nerve cells derived from human stem cells will also lead to a significant reduction in the need for experimental animals; this is also of great benefit to the people of California.